Abstract Acute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer, and a leading cause of death in children. Survivors of ALL experience substantial lifelong health risks compared to the general population. Understanding the causes of pediatric ALL in order to enable its early detection and prevention is therefore an important goal for improving both pediatric and adult health. A provocative recent report suggested an association of ALL with prenatal infection with cytomegalovirus (CMV) in a population-based sample of newborn dried blood spots (DBS) from 268 ALL cases and 270 controls in California. CMV was detected in DBS of 26/248 (9.7%) of case but only 8/270 (3%) of controls for a highly significant odds ratio (OR) of 3.71 (95% Confidence Interval (CI): 1.71-8.95). This raises the important question as to whether subclinical prenatal CMV infection contributes to the development of pediatric ALL. Replication of this finding in a large population-based study is warranted. Innate immunity is a key factor in both the control of infection and surveillance of pre-leukemic clones. Central to this immune surveillance are high functioning Natural Killer (NK) cells. Killer Immunoglobulin Receptors (KIR) are specifically expressed on NK cells, and interaction between KIR and HLA dictates NK cell phenotype (insert review). This important element of innate immunity has been associated with susceptibility to infections, including CMV reactivation and transmission in pregnancy. However, there are conflicting reports on the role of KIR-HLA in pediatric ALL and to date there have been no studies that have simultaneously considered CMV and these functional genetic variants in innate immunity. To confirm an association of congenital CMV infection and ALL and to clarify the role of KIR-HLA in pediatric ALL, we propose to conduct a population-based study of 1158 cases and controls matched 4:1 on sex, race/ethnicity, and year of birth obtained from the Michigan BioTrust for Health. Dried blood spots (DBS) obtained at birth from both cases and controls will be assayed for CMV, KIR haplotypes, and known risk variants previously discovered in genomewide association studies. As cytogenetic subtype is not routinely collected by the Michigan cancer registry, we will obtain this information from six institutions in the state that treat pediatric oncology patients. Our specific aims are to: (1) Compare CMV prevalence at birth in newborn DBS of ALL cases to that in controls and (2) Compare KIR-HLA genotypes among cases and controls. In addition we have two exploratory aims to: (1) Examine whether KIR-HLA genetics modify the association between congenital CMV infection and ALL and (2) Describe the association of KIR-HLA variants with CMV prevalence at birth. Confirmation of an association between congenital CMV infection and development of ALL will for the first time establish a potentially modifiable risk factor for the most common childhood cancer, as well as adding urgency to ongoing efforts to detect and mitigate the effects of congenital CMV infection.